1. Field of the Invention
The present disclosure relates generally to activities of microRNA-125b and various uses of miR-125b arising therefrom. For example, miR-125b can be used to modulate innate and adaptive immune responses by regulating activation and/or function of macrophages.
2. Description of the Related Art
MicroRNAs (miRNAs) are a recently discovered class of small RNA molecules that are emerging as potent regulators of multiple aspects of cellular function. mRNAs are evolutionarily conserved and have been found to be involved in post-transcriptional gene repression. See, e.g., Bartel, Cell 116: 281-297 (2004); Ambros, Nature 431: 350-355 (2004); Farh et al., Science 310: 1817-1821 (2005). In animals, miRNAs are processed from larger primary transcripts (pri-miRNA or pri-miR) through an approximate 60-bp hairpin precursor (pre-miRNA or pre-miR) into the mature forms (miRNA) by two RNAse BI enzymes Drosha and Dicer. See, e.g., Gregory et al., Nature 432: 235-40 (2004); Chendrimada et al., Nature 436: 740-744 (2005). The mature miRNA is loaded into the ribonucleoprotein complex (RISC), where it typically guides the downregulation of target mRNA through base pair interactions. Pri-miRNAs are transcribed by RNA polymerase II and predicted to be regulated by transcription factors in an inducible manner. Lee et al., Embo. J., 23: 4051-60 (2004); Fazi et al., Cell 123: 819-31 (2005); O'Donnell, et al., Nature 435: 839-43 (2005). While some miRNAs show ubiquitous expression, others exhibit only limited developmental stage-, tissue- or cell type-specific patterns of expression. See, e.g., Pasquinelli, Curr. Opin. Genet. Dev., 15: 200-205 (2005). In mammals, miRNAs have been associated with diverse biological processes.
Macrophages are key components of the mammalian innate immune system, acting to release cytokines, kill pathogens directly, and present antigens to the adaptive immune system. The macrophage surface contains sensing proteins, like TLRs and IFN-γR that, when engaged, lead to a rapid differentiation event termed activation, in which the cell transforms from relative quiescence to an effector state characterized by far-heightened microbicidal ability. Macrophages also carry co-stimulatory proteins such as CD80 and CD86 for interacting with T cells, thus bridging innate immunity to adaptive immunity. Several microRNAs have been shown to be mediators of the macrophage activation process. O'Connell et al. Nat. Rev. Immunol. 10:111-122 (2010); O'Neill et al., Nat. Rev. Immunol., 11:163-175. miR-155, -146, -147, -9, and -21 are induced by ligands of the TLRs. O'Connell et al., (2010); O'Neill et al., Nat. Rev. Immunol., 11:163-175 (2011). These microRNAs, in turn, inhibit expression of signaling proteins in the inflammatory signaling cascade, thus modulating immunity through feedback regulation. miR-125b, a homolog of the Caenorhabditis elegans microRNA lin-4, has been shown to be decreased in macrophages in response to TLR4 signaling. Androulidaki, Immunity, 31: 220-231 (2009); Tili et al., J. Immunol., 179: 5082-5089 (2007); Murphy et al., J. Immunol., 184: 5029-5037 (2010).